pH-responsive Targeted nanoparticles release ERK-inhibitor in the hypoxic zone Sensitizes Gemcitabine in Mutant K-Ras-addicted Pancreatic Cancer

Abstract

Abstract Therapeutic options for managing Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, are limited and disappointing. Therefore, despite suboptimal clinical effects, Gemcitabine (GEM) remains the first-line chemotherapeutic drug in the clinic for PDAC treatment. The therapeutic limitations of GEM are primarily due to poor bioavailability and the development of chemoresistance resulting from the addiction of mutant-K-RAS/AKT/ERK signaling-mediated desmoplastic barriers with a hypoxic microenvironment. Several new therapeutic approaches, including nanoparticle-assisted drug delivery, are being investigated. In this study, we designed pH-responsive nanoparticles composed of PEG-b-poly (carbonate) block copolymer encapsulated ERK inhibitor (SCH772984). Nanoparticles surface functionalized with tumor-penetrating peptide, iRGD, to target PDAC tumor tissue specifically. We used these nanoparticles to perform a combination drug treatment of GEM and ERKi. We found that the pH-responsive targeted nanocarrier efficiently released ERKi in hypoxic and low-pH environments. We also found that the free GEM, combined with nanoencapsulated ERKi, demonstrated significant synergistic outcomes in vitro and in vivo and impaired desmoplastic regulatory factors production in PDAC cells. In particular, the combination approaches significantly enhanced the GEM effect in PDAC growth inhibition and prolonged survival of the animals in the KPC mouse model.